Transdermal Drug Delivery System PDF

INTRODUCTION The increasing frequency of many diseases has led to notable breakthroughs in drug delivery technologies. A controlled drug delivery system called TDDS allows for quick, comfortable administration and, if systemic toxicity demands it, a painless termination. TDDS offers consistent plas...

INTRODUCTION The increasing frequency of many diseases has led to notable breakthroughs in drug delivery technologies. A controlled drug delivery system called TDDS allows for quick, comfortable administration and, if systemic toxicity demands it, a painless termination. TDDS offers consistent plasma drug concentration and fewer adverse effects than oral and parenteral drug delivery methods. This makes it possible to keep therapeutic medication concentrations above the minimal adequate concentration for a prolonged period. Additionally, medications administered via transdermal drug delivery systems (TDDS) can increase the drug's bioavailability by avoiding the pH variations during gastric transit's impact, digestion enzymes, and hepatic metabolism. Often referred to as patches, transdermal drug delivery systems (TDDS) are dosage forms intended to distribute a therapeutically effective medication dosage into the patient's skin. The human skin's entire morphological, biophysical, and physicochemical makeup must be considered when administering therapeutic medications for systemic effects because transdermal distribution prevents first-pass metabolism and improves patient compliance. Provides a noteworthy benefit in comparison to injectables and oral techniques. Furthermore, transdermal administration prevents pulsed absorption into the systemic circulation, enabling the continuous distribution of medications with short half-lives in the body. It frequently has unwanted side effects. As a result, many innovative medication delivery methods, including transdermal, controlled-release, and transmucosal delivery, were developed. Transdermal drug administration has several significant benefits, including limiting hepatic first-pass metabolism, improving therapeutic efficacy, and preserving the medication's stable plasma level. The first transdermal patch was created in the 1970s and given FDA approval in 1979 to treat motion sickness. Scopolamine was applied as a patch for three days. In 1981, a license for nitro-glycerine patches was first issued. The following patches are available today: nitro-glycerine, clonidine, fentanyl, lidocaine, nicotine, oestradiol, oxybutynin, scopolamine, and testosterone. Moreover, combined patches for contraceptive and hormone replacement therapy are developed. Depending on the drug, the patches might last from one to seven days. Transdermal drug delivery provides several significant advantages, including better bioavailability, more stable plasma levels, a longer duration of action that minimizes the need for frequent dosing, fewer side effects, and enhanced therapy because plasma levels are sustained until the end of the dosing interval, whereas levels with traditional oral dosage forms decrease. Transdermal patches have proven effective in minimizing first-pass drug-degradation effects and in finding novel uses for current therapies. Additionally, patches might mitigate adverse impacts. For example, oestradiol patches which each year are utilized by over a million people do not harm the liver in the same way as oral equivalents do. The markets for aroma patches, weight loss patches, thermal and cold patches, nutrition patches, skin care patches (which include patches that measure UV exposure), and non-medicated patches, have two major divisions: medicinal and cosmetic When comparing transdermal delivery to oral drug delivery, there are multiple advantages. It is specifically utilized in cases where the liver exhibits a notable first-pass effect that could make drugs metabolized too soon. Hypodermic injections, which cause pain, produce dangerous medical waste, and increase the risk of disease transmission by sharing needles, particularly in developing nations, are preferable to transdermal delivery. Non-invasive and self-administrable are further features of transdermal technology. They can offer relief for extended periods for as long as a week. Additionally, Patients' compliance is increased by them, and most systems are affordable. The largest challenge may be that very few medications can be distributed transdermally. Effective transdermal medications have molecular weights of only a few hundred Daltons, lipid-heavy octanol-water partition coefficients, and daily dosage requirements of 1-4 milligrams or less when administered using the existing delivery modalities. Transdermal administration of peptides and macromolecules has presented several unique issues, such as sophisticated genetic therapies utilizing small-interfering RNA or DNA. It has been challenging to utilize this route for the delivery of hydrophilic medicines. The distribution of vaccines is a further subject of intense curiosity. Through administering vaccinations to skin immunogenic Langerhans cells, transdermal administration may enhance immune responses while circumventing the need for hypodermic needles. It would also be possible to offer modulated or pulsatile delivery, which would entail feedback control, given the external location and patient regulation over patches. In both the US and Europe, iontophoresis—a pain management method that entails patient-regulated, electrically modulated fentanyl delivery has received approval for usage. Lastly, there is the potential to remove molecules (analytes) through the skin in addition to administering medication. This has previously been done for glucose monitoring with electrically extracted interstitial fluid, and other methods such as ultrasound have been investigated in clinical settings. This form of drug delivery system has advantages over conventional ones since it can store small amounts of pharmaceuticals in the transport and delivery structure, which is constructed by nanotechnology employing principally polymeric nanomaterials made with biopolymers, microneedles, and nanoparticles. Its most creative aspect is that the device is only needed to change when the dosage is finished, which may take many days. Advantages of Transdermal drug delivery system: 1. Prevent the first-pass metabolism. 2. A steady and regulated blood pressure. 3. Similar qualities to intravenous infusions. 4. Simplicity of terminating the medication's effect, if needed. 5. Extended activity times (from a few hours to a week). 6. No disruption of the intestinal and stomach fluids. 7. Fit for administering medications with a) remarkably short half-life. Like nitro-glycerine b) Limited time frame for therapy. c)The oral bioavailability is poor. Disadvantages of Transdermal drug delivery systems This route should not be taken when 1. The dosage of the drug is high. 2. The drug's higher molecular size hinders absorption; ideally, it should be less than 800-1000 Daltons. 3. The medication irritates and sensitizes. 4. The skin metabolizes the drug. 5. The drug binds to proteins in the skin. The following characteristics affect transdermal delivery: Drug release from the carrier. Crossing the barrier of the skin. The pharmaceutical response being triggered. STRUCTURE OF SKIN AND BARRIERS: The human body's largest organ is the skin, covering about 2 mŲ on its surface and making about 15% of the body's mass overall. Since the dawn of humanity, a variety of compounds have been applied to the skin's surface for therapeutic or religious purposes, suggesting that the skin's ability to absorb substances has long been understood. Human skin's barrier qualities, which are primarily provided by its horny layer (SC), can be seen as either a benefit or a drawback depending on the situation. The skin may come into contact with a variety of solid, liquid, or gaseous substances during daily living. Certain substances, such as allergens, toxic chemicals, and infections, can cause irritation, burns, rashes, and other health issues when applied topically or if they seep into the skin's deeper layers. Owing to the skin's enormous surface area (about 2 m2), topical drug dosing appears to be an intriguing alternative to oral treatment; yet, this approach is far from simple due to the skin's barrier function. It serves as an obstacle to permeability that prevents various biological and chemical materials from being absorbed transdermally. Which, ▪ differentiates the external surroundings from the blood circulation network beneath. ▪ Acts as a defense against biological, chemical, and physical attacks. ▪ Maintains body temperature by acting as a thermostat ▪ helps control blood pressure ▪ shields the skin from UV radiation. ▪ Skin plays a significant role in influencing several elements of medication administration, such as drug penetration and absorption through the dermis. The skin's ultrastructure and architecture have a major impact on its diffusional resistance. Anatomy of Skin: Four primary layers make up the structure of human skin: The non-viable epidermis, or stratum corneum, the healthy outer layer, the dermis that covers it is the highest layer of subcutaneous fat (Hypodermis). Epidermis The epidermis is the outermost layer of skin is called the epidermis. the skin's outermost layer. The continuously self-renewing, stratified squamous epidermis covers the entire body's exterior. It is mostly made up of two parts: the dead cells of the stratum corneum and the viable, or living, cells of the malpighian layer, also known as the viable epidermis. sometimes known as the horny layer. The layers known as stratum spinosum, stratum granulosum, stratum lucidum, and stratum basale, the innermost layer, comprise the stratum corneum, the outermost layer of the epidermis. The lowest layer is called the stratum germinativum, or stratum basale. Hemidesmosomes bind the basement membrane, which divides the stratum basale from the dermis. The epidermis and skin appendages, in particular the sweat glands and hair follicles that provide an alternate route to the intact epidermis, are among the skin penetration routes. The appendages of the skin comprise merely 0.1% of the skin's total surface area, and they have a negligible effect on the flow of medications that penetrate the skin. Hypodermis The dermis and epidermis are supported by the hypodermis or subcutaneous fat tissue. It acts as a fat storage facility. This layer offers nutritional support, and mechanical protection, and aids in controlling body temperature. Principal blood arteries, nerves, and maybe sensory pressure organs are carried to the skin by it. The medicine must enter the systemic circulation and pass through all three layers for transdermal administration to occur. Dermis The layer of skin immediately beneath the epidermis is called the dermis, and it ranges in thickness from 3 to 5 mm. It is made up of a matrix of connective tissues, including blood arteries, lymphatics, and nerves. An important role for the cutaneous blood supply is to regulate body temperature It provides the skin with nourishment and oxygen in addition to getting rid of waste and contaminants. Capillaries, which extend to less than 0.2 mm from the skin's surface, are where most molecules that breach the skin barrier find a sinking state. Consequently, the blood supply maintains an exceptionally low cutaneous concentration of permeate. The critical driving factor for transdermal permeation is the consequent concentration differential across the epidermis. This layer, which is commonly thought of as gelled water in terms of transdermal drug administration provides a moderate impediment to the majority of polar medications' distribution Nevertheless, when delivering very lipophilic substances, the cutaneous barrier might be significant. The dermis and epidermis are separated by a basement membrane. Understanding dermal absorption is important for substances that may come into contact with the skin to calculate systemic exposure and conduct risk assessments.  Fig 1: Structure of skin layers Skin barriers: Drugs that are released in transdermal formulations penetrate the skin and reach the bloodstream. For transdermal therapy to be successful, the drug must be absorbed in large amounts for plasma concentrations to be reached. In certain situations, drug penetration is intended to occur in areas of the body near the site of action, such as the muscles, blood vessels, and articulations, where a localized effect is anticipated. In this sense, the total amount of medication that permeates and penetrates the skin is appropriately described by the term "cutaneous absorption". First, the outermost layer of skin, the stratum corneum, has the epidermis's skin barrier effect, which is the capacity to keep substances from the outside. When it comes to the transportation of chemicals with a high molecular weight, the barrier effect is crucial. It is commonly known that TDDS delivers molecules with small molecular weights through the intracellular pathway. On the other hand, methods and other processes that make use of both intracellular and intercellular pathways are presented and utilized for medications with extremely large molecular weights. This is caused by the way the skin is structured, since the lipid layer, comprises both hydrophilic and hydrophobic molecules in addition to cellsis regular even though it is not totally regular in its existence. The physicochemical qualities that are tried to improve drug transport through the skin can explain these structural aspects. Next, transdermal transport may be impeded by the vascular system in the skin layer. Although topical administration is the clear choice when treating dermatological diseases, it has also been proven that pharmaceutical drugs administered topically travel into the bloodstream. Barrier function can be disrupted by physical, chemical, and pathological variables, For the barrier to function, the stratum corneum's structural integrity must be maintained. The outermost layer of the epidermis called the stratum corneum (SC), acts as the primary barrier against permeability. SC reduces water loss and shields against external substances that could cause infection or injury. Trauma or illness-related skin damage weakens the SC and increases the epidermis's permeability to medications. Because the SC is composed of 10–15 layers of corneocytes, lipid matrix, corne desmosomes, and tight junctions, it is thick and impervious to drug molecules. As a result, getting the medication past the SC barrier, onto the skin, and letting it spread until it reaches the dermal blood vessels is the most difficult part of using TDDS. The problem is that TDD's application in clinical practice is restricted because so few medications can pass through the skin. As a result, several other approaches, such as chemical and physical techniques, have been looked into to get over the SC barrier. There are two categories of techniques used to alter the SC's barrier characteristics: chemical and physical methods. The dead stratum corneum cells, which limit the transport of pharmacological molecules both within and outward and have a high electrical resistance, are the primary obstacles to absorption. The physical barrier is made up of tight junctions (TJs) and the stratum corneum (SC). From the inside out, TJs constitute the first physical barrier, although the majority of the epidermis' defensive properties are exerted by the SC from the outside in. The keratinocytes, skin resident immune cells, and Langerhans cells work together to form a secondary immunological barrier in the event of a barrier deficit. The epidermal keratinocytes' release of defense chemicals plays a part in the skin's ability to maintain its chemical barrier. the skin microbiome is considered a microbial barrier; we will quickly go over these four barrier functions. 1. Physical barrier 2. Chemical barrier 3. Immunological barrier 4. Microbial barrier 1. Physical barrier With intermediate lipid layers in between, 15 to 20 stacked layers of corneocytes make up the SC. Viable keratinocytes undergo terminal differentiation, whereupon they become dead, dying cells known as corneocytes, without their cytoplasmic organelles and nuclei. inhibitors of proteases, such as cystatin M/E, and enzymes like transglutaminases (TG’ases) control the desquamation and cornification processes in keratinocyte terminal differentiation. The latter stages of lipid synthesis take place near the junction between SC and the viable epidermis, and the lipids are an essential component of the physical barrier. In the various layers of the epidermis, keratinocytes express different epidermal proteins during the differentiation process. This feature is highly helpful for identifying the layers in human skin models' epidermis and determining whether or not the epidermis created in vitro accurately resembles native skin. Additionally, through adherens junctions, TJs, and desmosomes, the viable epidermis supports the operation of the epidermal barrier. Desmosomes and adherens junctions are crucial for the attachment and differentiation of keratinocytes, which are necessary for maintaining the integrity of the epidermis but unrelated to the skin barrier's operation. The skin barrier function depends on TJs, just as the inside-out barrier function does. The creation of TJs in the granular cell layer by numerous TJ proteins, each expressed at distinct layers of the epidermis, demonstrates the intricacy of skin barrier construction. 2. Chemical barrier The skin contains immune cells that prevent bacterial infections and keratinocytes that produce antimicrobial peptides (AMPs Keratinocyte-derived AMPs that are most widely recognized include Defensins, human cathelicidin LL-37, S100 proteins, and late cornified envelope proteins. Secretory leukoprotease inhibitors (SLPI), dermcidin, and SKALP/elafin are other skin AMPs. Skin homeostasis results in the absence or minimal expression of the majority of these AMPs. When these AMPs are expressed more powerfully to support the host's defense, they are found in more vulnerable locations such as the hair follicles (port d'entre) or internal epithelia (oral cavity, vagina). Reactive oxygen species (ROS), which are formed by keratinocytes and have antibacterial properties, are part of the chemical skin barrier. However, when ROS are produced by excessive UV radiation, they can also be harmful to the host. To defend itself, the skin produces antioxidants including vitamins C and E, ROS scavengers like superoxide dismutase, catalase, and peroxidase, and glutathione. Furthermore, It has been shown that by efficiently inhibiting ROS in the epidermal cornified cell membrane, small proline rich (SPRR) proteins contribute significantly to epidermal protection. 3. Immunological barrier Both the innate and adaptive immune systems' cells and molecules are found in the dermis and epidermis to provide opposition to numerous pathogens. The formation of pattern recognition receptors is one such defense mechanism; these receptors can bind ligands generated by bacteria to trigger an immune response. I.e. Apart from immune cells that support epidermal host defense, like patrolling T cells in the epidermis or Langerhans cells, keratinocytes are powerful producers of soluble immunomodulatory factors, like chemokines and cytokines that either promote or inhibit inflammation or that can affect T cells and dendritic cells. Research on the interaction between immune cells and keratinocytes has been ongoing for many years since it is necessary for both inflammatory processes and tissue homeostasis. T cells are twice as abundant in the skin as they are in the blood, highlighting the skin's significance as an immune reservoir. 4. Microbial barrier The commensal skin microbiome forms the microbial barrier. The entire microbiota that lives on our skin, which is mostly made up of bacteria but also contains fungi and viruses, is referred to as the skin microbiome. Our skin's natural defenses against harmful germs act as a barrier. Human health is enhanced by a well-balanced microbiome, and several studies have shown a connection between illness and disequilibrium, with a change in favor of harmful bacteria. The primary focus of the study is on the intricate interactions between microbes and hosts on the surface of human skin in both health and disease. Pathways for Skin Penetration : The skin's barrier function isn't perfect in preventing topical medications from being fully absorbed. It is commonly recognized that a substance given topically to the skin can permeate the skin through three different routes: a. Hair follicle route b. Intercellular route c. Intracellular route. The duration, frequency, and solubility of the medication in each domain dictate the significance of these channels for transcutaneous drug absorption. 1. The Shunt Route Hair follicles can act as a conduit from the epidermis to the dermis because of their base-connected connection to systemic blood circulation. Penetrants can penetrate through the stratum corneum thanks to a "shunt" channel created by sweat glands or hair follicles. 2. Intracellular Route Intercellular lipids follow penetration through corneocytes in the intracellular (transcellular) pathway. Compounds arriving via this route exploit the corneocytes' flaws, which result in water-filled apertures. Because corneocytes' lipid intercellular layers are so poorly permeabilized and because it's necessary to occasionally separate the more hydrophilic corneocytes from them, the stratum corneum, and vice versa; nonetheless, this is not considered the preferred path of dermal diffusion. The use of a penetration enhancer may alter corneocytes' protein composition and, as a result, their permeability, making the intracellular route more crucial. 3. Intercellular Route Most chemicals enter the body primarily through the intercellular channel, particularly once steady-state requirements are met. By diffusing between viable cells in the dermis, the stratum corneum's horny cells, and the epidermis, solutes travel through intercellular lipid domains. Tracer investigations indicate that the primary barriers to epidermal permeability are not corneocyte proteins, but rather intercellular lipids. Tracer investigations indicate that the primary barriers to epidermal permeability are not corneocyte proteins, but rather intercellular lipids. The intercellular channel was eventually disregarded as the main mechanism of skin permeation because of its low volume of occupancy. Subsequent research revealed that the volume percentage between cells was far higher than initially thought. These findings imply that a substantial barrier to skin penetration is provided by the intercellular pathway. PENETRATION ENHANCERS When pharmaceuticals are applied topically, they come into touch with and penetrate the epidermis and dermis, which include dendritic cells that are essential for immunological responses. Using penetration enhancers and fractional mode laser and light devices are two methods to improve and facilitate transdermal medication permeation. The properties of penetration enhancers, which help drugs pass through the skin more easily, possessing a specific mechanism of action, being pharmacologically inactive, largely odorless and colorless, physical and chemical stability, nontoxicity, non-irritating, non-allergenic, and reversible action. enhancers mainly affect the stratum corneum, where they might alter medication distribution or partitioning. The most often used penetration enhancers are alkanes, fatty acids, terpenes, cyclodextrins, surfactants, and azone, among other substances. It is generally accepted that PEs can increase a drug's skin penetration by acting on the SC intercellular lipids through fluidization or extraction, enhancing the drug's SC partitioning, or changing the conformations of keratinized proteins. The stratum corneum (SC), in particular, has a barrier characteristic that blocks transdermal drug delivery (TDD) the most. Various methods have been researched and developed to enhance the skin's ability to absorb pharmaceuticals. The most widely used strategy among them is the use of penetration enhancers (PEs). The physical chemistry of skin penetration : Diffusion is a passive kinetic process that moves from a region of high concentration to a region of lower concentration along a concentration gradient. Equation (1), which is Fick's first law, describes steady-state diffusion. According to this equation, the rate of transfer (or flux, J) of the diffusing substance via area A of the membrane unit determines the molecular velocity across the diffusional medium (or diffusion coefficient, D) and the concentration gradient across the membrane (dC/dx). J = −AD (dC/ dx) (1) Since the process of diffusion moves against the direction of greater concentration, Eq. (1) has a negative sign. From Eq. (1), one can create Fick's second law of diffusion, at times designated as Eq. (2), which explains membrane transport in situations including nonsteady states. The rate of change in the concentration gradient and the concentration change over time are related by the following partial differential equation: 𝑑𝑐 = D ( ∂2C /∂x2 ) (2) 𝑑𝑡 When a certain mixture is administered topically, the concentration profiles of a permeant can change over time and be described using an analytical response to Equation (2). Eq. (2) perhaps rewritten as Eq. (3) in the case where In order to sustain sink conditions in the receptor compartment and deliver the medication to the membrane at a steady state, maximum fixed concentration in the donor compartment: J = AD (Cm/h) (3) where Cm is the concentration of the substance at the donor-membrane interface and h is the effective diffusional pathlength of the membrane. The vehicle- membrane partition coefficient (K) can be further defined by utilizing the ratio of permeant concentrations in the membrane at the donor-membrane interface to the vehicle in which it is administered (Cv). This term can be used to substitute Cm in Eq. (3), resulting in Eq. (4), which describes steady-state flux across membranes and is a modified version of Fick's first rule of diffusion. It may come as a surprise that Fick's rules serve as such a useful framework for comprehending transfer via the skin given its intricate structure. Jss = ADKCv/ h (4) Eq. (4) indicates that a change in D, K, and C should result in higher drug flux for passive drug permeation enhancement. Consequently, substances that improve skin penetration have the ability to alter a drug's solubility, partitioning behavior within the SC, and/or diffusion characteristics. Higuchi (1960) noted that another method of controlling permeant flow is to modify the drug's thermodynamic activity in the formulation. Types of penetration enhancers Currently, several enhancement techniques are used to increase the permeability of pharmaceuticals; general categories of the enhancers are displayed. The most common kinds use drug vehicle-based, chemical, physical, natural, and bio- macromolecular techniques.  Fig.2 Types of penetration enhancers Table no.1: types of penetration enhancers Penetration Description Examples enhancers Physical procedures or Microneedles: The skin's enhancers physical microchannels are made by tiny pressures needles. employed in - Iontophoresis: Improves medication methods to distribution by applying an electric increase drug current. penetration. - Sonophoresis: Increases penetration by using ultrasonic waves. - Electroporation: The skin becomes temporarily perforated by electrical  pulses. - Laser Therapy: This method delivers drugs by creating microchannels with laser radiation. - Thermal Methods: Using heat to make skin more permeable. - Derma rollers: Rolling tools that improve medication distribution by incorporating microneedles. Chemical substances that Sodium Lauryl Sulfate (SLS): Lipid layer enhancers increase drug disrupting surfactant. absorption by - Ethanol: By causing lipid structures to chemically break down, it increases skin altering the permeability. mucosal or skin - Propylene Glycol: Promotes skin barrier. penetration and medication solubility. Dimethyl Sulfoxide (DMSO): A solvent that modifies lipid layers to enhance permeability. - Oleic Acid: A fatty acid that improves penetration by breaking down the skin's protective layer. - Azone: A chemical enhancer that messes with the arrangement of skin lipids. - Surfactants (such as Polysorbates):  Emulsifiers that increase the skin's absorption of drugs and their solubility. substances used - Lecithin: A phospholipid which helps to deliver drugs in the formation of drug-delivery to target liposomes. and come from - Chitosan: A biopolymer that interacts natural sources with mucosal surfaces to increase or biological permeability. molecules. - Hyaluronic Acid: A natural polymer that promotes the absorption of medications and keeps skin hydrated. Natural and - Cyclodextrins: Organic biomolecular oligosaccharides that combine with enhancers medications to form inclusion complexes. One protein that can be utilized to create drug carriers is gelatin. One polysaccharide utilized in medication delivery methods is pectin. Sodium Alginate: Drug delivery gels are produced from this natural polymer. Drug vesicles- systems that - Liposomes: Drug-encapsulating based enhancers more efficiently spherical vesicles that improve skin distribute penetration. medications - Nanoparticles: Small particles with through the skin increased cellular absorption that by using vesicles facilitate better medication delivery. or other - Niosomes: Drug delivery vesicles carriers. based on non-ionic surfactants.  Solid Lipid Nanoparticles (SLNs) are lipid-based nanoparticles that increase the penetration and stability of drugs. - Polymeric Micelles: Block copolymer- based micellar systems that enhance medication delivery and solubility. - Dendrimers: Branched macromolecules that encase medications to improve absorption. - Transferosomes: Pliable vesicles with enhanced skin penetration capabilities. Miscellaneous Other practices - Liposomes: Drug-encapsulating or materials spherical vesicles that improve skin that don't penetration. cleanly fall into - Nanoparticles: Small particles with the previously increased cellular absorption that mentioned facilitate better medication delivery. categories - Niosomes: Drug delivery vesicles based on non-ionic surfactants. Solid Lipid Nanoparticles (SLNs) are lipid-based nanoparticles that increase the penetration and stability of drugs. - Polymeric Micelles: Block copolymer- based micellar systems that enhance medication delivery and solubility. - Dendrimers: Branched macromolecules that encase medications to improve absorption. - Transferosomes: Pliable vesicles with enhanced skin penetration capabilities. The following are the ideal characteristics of penetration enhancers: They should be compatible with excipients and medications; Pharmacological inertness, allergy prevention, and nontoxicity are desirable qualities. It cannot act pharmacologically on the body in any way. It must be visually appealing. It needs to be tasteless, colorless, and odorless. It should function unidirectionally, allowing therapeutic drugs to enter the body while preventing the body from losing endogenous material. It needs to be physically and chemically stable; Its duration of action needs to be repeatable and predictable; and It needs to have strong solvent properties. POLYMERS USED IN TDDS Truly macromolecules, polymers are made up of enormous chains of carbon atoms joined by covalent bonds. There are many different uses for polymers in skin preparation. The different types of formulations determine which of these polymers are needed. The most common kinds of polymers used on skin are silicones, chitosan, carrageenan, polyacrylates, polyvinyl alcohol, polyvinylpyrrolidone, and derivatives of cellulose. These include gelling compounds, matrices for patches and dressings, penetration enhancers, and anti- nucleants. The fundamental components of a transdermal medication delivery system are polymers. Multilayered polymeric laminates are used to create transdermal delivery systems. Two polymeric layers, an outside layer that is resistant to drugs and prevents the loss of medicines through the backing surface, and an interior layer that serves as a rate-limiting membrane, glue, or both, encase a drug reservoir or drug-polymer matrix. The following three categories broadly describe transdermal drug delivery systems: 1. Reservoir systems This device consists of a drug reservoir and a rate-controlling membrane layered over an impermeable backing layer. Only the rate-controlling membrane, which may or may not be microporous, permits the release of medication. The drug may be dispersed as a gel, solution, suspension, or solid polymer matrix inside the drug reservoir compartment. A drug-compatible thin coating of allergen-free sticky polymers can be applied to the polymeric membrane's systems in matrices outdoors. Medication in an adhesive system. Before applying the medicated adhesive, the medication is first generated in the medication reservoir by either melting the adhesive (for hot-melt adhesives) or using a sticky polymer to disperse the medication. Polymer adhesive is applied onto an impermeable backing through melting or solvent casting. Layers of sticky, unmedicated polymer are put on top of the reservoir. 2. Matrix-dispersion system The medication is evenly distributed throughout a matrix of hydrophilic or lipophilic polymers. Next, instead of applying adhesive on the reservoir's front, the adhesive rim strip is made around the drug reservoir's perimeter, creating an adhesive rim strip, and Within a compartment having a drug-impermeable backing layer, the drug-containing polymer disk is attached to an occlusive base plate. 3. Micro-reservoir systems This medication delivery device integrates reservoir and matrix-dispersion technologies. drug reservoirs are constructed of millions of impermeable, microscopic spheres by suspending the drug in an aqueous solution of a water- soluble polymer, which is thereafter equally distributed within a lipophilic polymer. the cross-linking of the polymer stabilizes the thermodynamically unstable dispersion in situ. One of the unique drug delivery fields that is developing the fastest is transdermal drug delivery technology. Recent advancements within the discipline of polymer science are what are driving this rise. In order to assist formulators in selecting the appropriate polymers, this topic focuses on the physicochemical and mechanical properties of the polymeric materials utilized in transdermal delivery systems. Transdermal delivery systems employ polymers in several ways, such as matrix formers rate-controlling membranes pressure-sensitive adhesives (PSAs) backing layers release liners. Transdermal delivery systems require polymers that are both chemically and biologically compatible with the medicine and with other components of the system, including PSAs and penetration enhancers. Additionally, they must have a universally accepted safe status and provide medication in a reliable, and effective throughout the specified shelf life or delivery period of the product. A delivery tool set is more effective than a single delivery tool Economically 1. Matrix formers It is necessary to carefully study the design and selection of polymers to manufacture transdermal delivery systems that efficiently meet the various requirements. The most difficult task is designing a polymer matrix. Subsequently, the drug-loaded matrix is optimized concerning release characteristics, the balance between adhesion and cohesion, physicochemical features, skin compatibility, and stability, and other system components. When it comes to passive transdermal delivery systems, a monolithic solid-state design is typically chosen due to manufacturing concerns and aesthetic appeal. Polymeric matrices are utilized in transdermal delivery systems for encapsulating drug reservoirs, adhesion (like a PSA), and rate control to polymers that were employed, either with or without rate control, in the creation of matrices. 2. Cross-linked poly (ethylene glycol) (PEG) networks. For numerous biological uses, PEGs are the preferred polymers. because of their biocompatibility. PEGs crosslinked with tris(6-isocyanatohexyl) iso-cyanurate via a urethane–allophanate linkage can transport proteins and create polymer networks that can swell in phosphate-buffered saline or ethanol and gel. It has been demonstrated that these systems release the solutes bi-phasically. 3. Acrylic-acid matrices. Plasticizers and acrylic-acid matrices have been utilized to create drug-polymer matrix films meant for transdermal delivery. Several polymers, including Eudragit RL PM, Eudragit S-100, Eudragit RS PM, and Eudragit E-100, have been recorded. Eudragit NE-40D is a hydrophobic polymer that is non-adhesive and methyl methacrylate and ethyl acrylate copolymer has also been used as a matrix creation. In comparison, the square-root-of-time approach offers a more precise explanation of these matrix systems' medication release rates. 4. Ethyl cellulose (EC) and polyvinylpyrrolidone (PVP). To distribute indomethacin and diltiazem hydrochloride, e, EC, and PVP matrix films with a plasticizer of 30% dibutyl phthalate have been developed. When hydrophilic substances like PVP are combined with an insoluble film forming like ethyl cellulose, the release-rate constants of the former typically increase. This result can be explained by the soluble component leaching, which created holes and shortened the drug molecules' mean diffusion path length before letting them drop into the liquid for disintegration The outcome is increased rates of dissolution. PVP and other materials work as antinucleating agents, preventing medications from crystallizing too quickly. As a result, they contribute significantly to increasing a drug's solubility in the matrix by maintaining it in an amorphous state, which facilitates quick solubilization through dissolution medium penetration. 5. Hydroxypropyl methylcellulose (HPMC). Propranolol hydrochloride patches have been designed using hydrophilic swellable polymer, HPMC, which is also a matrix forming in oral controlled drug administration. HPMC has created clear films, most likely because the medication is sufficiently soluble in the polymer. During the dissolving test, HPMC matrices without rate-controlling membranes showed a burst effect because the medication spilled quickly due to the polymer's rapid hydration and swelling. 6. Organogels. Reverse micelles are frequently formed by a few non-ionic surfactants, including Tween, lecithin, and sorbitane monostearate. These surfactants go through association reorientation and gel when mixed with water in an organic solvent. One possible use for these organogels is as a matrix to administer medications transdermally with a higher influx as proposed by Bhatnagar and Vyas, propranolol may be delivered transdermally using soy lecithin in isooctane microemulsion based on reverse micelles that have been gelled with water. Compared to a petrolatum-based carrier, the transdermal flow of propranolol from this organogel rose tenfold. Organogels, which are utilized as matrices for the transdermal delivery of medications, were also reported by Willimann et al. These were created by adding a small quantity of water to a lecithin solution in organic solvents. This method yields isotropic and thermo-reversible gels that may dissolve amphoteric, hydrophilic, and lipophilic materials, including enzymes, at temperatures above 40o C. They have a lengthy half-life and are biocompatible. The following types of polymers are utilized in TDDS: 1. Natural polymers Natural polymers include things like chitosan, waxes, gums, zein, gelatine, shellac, and derivatives of cellulose 2. Synthetic elastomers Synthetic elastomers include butyl rubber, nitrile, acrylonitrile, silicon rubber, hydrin rubber, polyisobutylene, and polybutadiene. 3. Synthetic polymers Polyvinyl alcohol, polyvinyl chloride, polyethylene, polypropylene, polyacrylate, polyamide, polyurea, polyvinylpyrrolidone, polymethyl methacrylate, and other synthetic polymers are examples. Table 2: types of polymers RECENT ADVANCEMENT IN TDDS: In comparison to alternative administration methods, transdermal drug delivery presents several advantages, including self-administration simplicity and the potential to avoid first-pass metabolism. However, not all medications may be applied with a traditional transdermal administration due to the SC's thick cellular structure and hydrophobic qualities. a multitude of factors can impact a medication's ability to be absorbed via the skin. Permeation enhancement is the process of using external energy as a driving force or to lower the barrier character of SC. These methods hold the potential to improve transdermal delivery efficiency. The development of tiny, potent devices that can produce the necessary therapeutic response has been made possible by recent advancements in precision engineering (bioengineering), computer, chemical engineering, and material sciences. Evolution of transdermal patches There are now four generations of TDDS. 1. First generation: diffusion-based transdermal drug delivery Developed in the early 1970s, the initial generation of transdermal patches was quite simple. Following the FDA's approval, about 19 patches—including ones with nicotine, menthol, and oestradiol—are now offered for sale in the US received the first approval for the treatment of motion sickness using scopolamine patches. The natural distribution of medications serves as the foundation for the construction of the first generation of TDDS. Through natural diffusion, drugs go from TDDS to the skin, where they are absorbed and begin to work. The initial wave of TDDS was restricted to lipophilic, low molecular weight medications that were efficacious at low doses and concentrated on the drug's characteristics. With partition coefficients greater than 104, extremely small particle sizes, and molecular weights of no more than 400 Da, the majority of first- generation transdermal medications are extremely lipophilic. Although it has a narrow range of applications, the previous transdermal delivery method, which was based on the physicochemical properties of pharmacological molecules, has shown promise in medical applications. Consequently, Considerable efforts have been made to increase the number of drug candidates appropriate for transdermal application and to enhance the effectiveness of their administration. 2. Second generation: non-invasive transdermal drug delivery with actuation To improve drug delivery's effectiveness from both the drug and the SC perspectives, the second generation of TDDS, which gives an additional driving force for drug entry into the skin or is based on the reversible breakdown of the SC structure, was developed to boost other tiny molecules' transdermal transport capabilities medicines made of molecules. To attain better transdermal drug delivery efficiency and to make it easier for medications to flow through the skin, the medication is first adjusted to have an appropriate log P value. second, some physicochemical processes cause the SC's structure to break or create pore channels. While certain limitations persist, second-generation therapeutic delivery systems (TDDS) have paved the way for maximizing drug delivery effectiveness. Using chemical enhancers or external energy sources, second-generation transdermal administration techniques aim to maximize medication permeability to the skin while avoiding skin structure damage. Chemical enhancers increase the drug's solubility and interact with the proteins that make up the skin to help the medication penetrate the skin. In contrast to skin irritants such as oxazolidinone, dimethyl sulfoxide (DMSO), and dimethylformamide (DMF), safer chemical enhancers such as fatty acids, Applications for urea and pyrrolidone are already available. One of the main techniques for non-invasive transdermal distribution is emulsion, which dissolves a variety of hydrophilic and lipophilic medications in a transdermal formulation. The surface charge, composition, and droplet size all affect an emulsion's absorption profile. It has been particularly appealing to reduce vehicle particle sizes to the micrometer or nanoscale level since smaller droplets are more likely to be able to pass through the epidermal barrier's tightly packed layers. Recently, researchers have looked into the potential uses of nanomaterials for the controlled release and transportation of various medications, such as cancer, antibiotics, and nucleic acid therapy. It has been particularly appealing to reduce vehicle particle sizes to the micrometer or nanoscale level since smaller droplets are more likely to be able to pass through the epidermal barrier's tightly packed layers. For instance, drug-loaded nanoparticles (NPs) can carry an encapsulated mixture of capsaicin and siRNAs that reduce inflammation by successfully crossing of the epidermal barrier. On the other hand, the stratum corneum impeded the transport of the siRNA capsaicin combination in solution form. Using nanoscale vehicles that respond to physicochemical cues can improve the efficacy of drug delivery control. As an example, consider the temperature-responsive nanogel, which dramatically enhances the medication's release as the temperature drops from room temperature to skin temperature. A further technique for stimuli-responsive The pH-sensitive release of antibacterial drugs into the skin is known as drug release in reaction to a pathogenic biofilm's acidic environment. To achieve synergistic efficacy in transdermal distribution, patches are integrated with stimuli-responsive nano-vehicles. In addition to encouraging a faster rate of drug absorption, external stimuli like light, mechanical force, and magnetic fields also make it easier to start and stop drug administration. A transdermal patch's ability to release medication can be triggered by visible light. For instance, drug- loaded hydrogels are capable of reacting to light-induced temperature changes. Controlling the external stimuli can readily turn on and off medication transport in addition to increasing cumulative delivery. As an alternative, the transdermal patch's medication release can be managed by mechanical force. The patch undergoes lateral strain and releases the medication as the joints flex. Medicinal patches can be integrated with external devices, especially wearable ones. The energy delivered by the devices is high enough to encourage drug dispersion through the skin. Drug-delivering locomotives are often electrically and thermally powered devices. For instance, the skin penetration of the medication may be improved by localized heat via a wearable heater. The solubility and diffusivity of both organic and inorganic medicines rise from the drug-containing layer when heat is applied. The transdermal medications penetrate the body more readily when heat is used because it also promotes blood vessel wall permeability, circulation of bodily fluid, and rate-limiting membrane permeability. By measuring the flow of fentanyl applied topically, a strong opioid analgesic, at 32 and 37 °C, for instance, the influence of temperature was assessed in vitro. The medication flow about quadrupled during the 5 °C temperature increase. Subsequent investigations reveal that a 5 °C temperature shift is required to produce a discernible improvement in drug transport and permeability between cell membranes. Iontophoresis increases and regulates the entry of charged medications across the epidermal barrier by means of an electrical current. Easily adjust the dosage by varying the stimulating current's strength and duration. Cryo-electrophoresis is a new technology that reduces the danger of skin burns by administering a high current to locally frozen skin, increasing electrophoretic efficacy. Nevertheless, the efficiency of drug administration is not significantly increased by non-invasive transdermal distribution, especially for hydrophilic and high molecular weight medicines (such as proteins). 3. Third generation: minimally invasive transdermal drug delivery A subset of TDDS created specifically for SC is called third-generation TDDS. By targeting SC via physicochemical or other processes, they can enhance the effectiveness of transdermal medicine administration without jeopardizing deeper tissues. Third-generation TDDS substantially improves the inadequacies of TDDS in drug delivery by allowing the transdermal delivery of tiny molecules and macromolecular drugs and vaccinations. Once the drawbacks of non-invasive transdermal distribution have been acknowledged, minimally invasive transdermal delivery is becoming a popular substitute strategy. The stratum corneum is disturbed in minimal epidermis invasion. to keep epidermal disruption at a clinically safe level and to more effectively transport hydrophilic medications and macromolecules into the inner skin. Currently, many kinds of microneedles and high-power radiation modalities (such as radiofrequency (RF), ultrasound, and laser) are being used to puncture or disturb the skin and improve medication delivery. But to facilitate the skin's quick healing, skin damage should be kept to a minimum and constantly monitored. Using ibuprofen as a model medication, a comparative investigation discovered that there can be notable variations in the biodistribution and bioavailability of microneedles manufactured in various ways. In terms of bioavailability, minimally invasive microneedles outperform non- invasive iontophoresis. The variety of medications that can be administered through the skin is increased when high-strength electricity disrupts the epidermis. The outer layers of the skin require a notably high energy level to cause damage, so it's important to carefully regulate the applied energy's amplitude and exposure duration to avoid inadvertently damaging the inner layers of the skin. During radiofrequency ablation (RF ablation), the outer layer of the skin is temporarily heated using a high-frequency electrical current (100–500 kHz). Ultrasound is used in sonophoresis to create heat and facilitate the transport of medication into the skin. In contrast to single-frequency ultrasound, double- frequency ultrasound has recently been employed to improve skin permeability and reduce treatment duration. Laser ablation is widely used in the cosmetics industry to treat acne, remove hair, and resurface skin. The laser points a high- energy beam at a precise location to puncture the skin. Near-infrared light is absorbed by gold nanorods, which produce a strong heat that can harm the skin's outer layer. Pulsed lasers just increase the skin's surface temperature and cause less inside skin damage than continuous-wave lasers. Despite the encouraging outcomes of RF ablation, sonophoresis, and laser ablation procedures, their application in clinics is restricted by the huge and expensive equipment needed. On the other hand, due to their affordability and ease of use, microneedles have garnered a lot of interest as a minimally invasive medication delivery method through transdermal application. Compared to high-power energy modalities, microneedles are less unpleasant for the skin and easier to employ. Furthermore, depending on the needs of the patient, microneedles allow for the controlled and sustained delivery of medications. Depending on how they are used and fashioned, microneedles can be classified as solid, hollow-shaped, surface-coated, dissolvable, or smart. Metals and silicon are examples of hard materials used to create solid microneedles. The materials' hardness makes it simple for the solid microneedles to form micropores, the tiny openings by which medications are delivered. Since the micropores are recovered quickly after formation, more patches or medications (such as diclofenac) can be used to prolong the micropore formation process. A medication that has been deposited on the solid needle substrate's surface may likewise be incorporated into microneedles. The coating layer limits the amount of medication loaded onto the needles' surface by weakening the needles' physical strength and sharpness. For treatments like vaccine delivery and cosmetic operations, where significant volumes of medicines do not need to be administered, coated microneedles are utilized. Dissolvable microneedles are made of biocompatible and water-soluble polymers. The polymeric matrix of dissolvable microneedles encapsulates drugs, which are produced when the matrix gradually dissolves in physiological fluids or deteriorates. By choosing the right polymers, the temporal drug release profile can be regulated from a few seconds to several months. However, there are disadvantages to this approach as well. The medications loaded in the polymeric precursor can be denatured, for instance, if the polymer for microneedles is cured using ultraviolet (UV) irradiation or heated to a high temperature during the production process. Because adding a substantial amount of drug to the precursor mixture would reduce the mechanical strength of the needles, the amount of drug that may be added to the polymeric matrix is likewise restricted. The medication solution runs through a hollow core located inside hollow microneedles. Pressure- driven flow is one active way for the medication solution to enter the needle hole, while diffusion is the passive way. A pump is used to release the medicine from a reservoir that is affixed to the rear of the microneedles. There is value in using hollow microneedles to regulate the dosage of administered medication. But one drawback of this method is that extra apparatus (such a drug reservoir and pump) is needed to help the microneedles administer the medication. Microneedles are a significant advancement in transdermal distribution, offering a wider range of viable medication options and greater efficiency and adaptability. The mass production fabrication method hasn't been decided upon yet, though. Moreover, transdermal patches, which are the only means of controlling the offset of drug release, have the same restrictions that apply to microneedles. Adding other technology components might make it feasible to imagine a more dynamic, feedback-controlled, pulsatile, and adjustable release profile for the medication. 4. Fourth generation: controlled and feedback-induced transdermal drug delivery The most sophisticated TDDS available right now are fourth-generation TDDS, which combine bioelectronic technology with intelligent wearables. which, in terms of optimizing transdermal medication administration, are identical to the second and third generations. This is especially true as they may cleverly adjust medication distribution by constantly observing the body's signal level. The skin barrier is gradually broken down, the range of drugs that can be used is increased, and drug delivery efficiency is optimized Between the first and fourth generations of TDDS, skin irritation is reduced and transdermal drug delivery safety is increased. Real-time drug delivery monitoring is achievable even with fourth- generation TDDS thanks to the aforementioned advantages. This is unquestionably a TDDS first an intelligent drug delivery system that is both smart and controllable. The capacity of personalized therapy to tailor care according to the unique pathophysiological circumstances of each patient sets it apart from traditional medical interventions. To establish individualized therapy, monitor the progression of the illness, and evaluate the efficacy of the drug, the dosage needs to be meticulously altered in response to precise, in-the-moment physiological parameter monitoring of the patient. The enhanced transdermal delivery system powered by soft bioelectronics has been highlighted as a method for the future generation of pharmaceutical administration technology in response to the growing requirement for tailored therapy. The swift progression of soft and ultrathin wearable gadgets has made it easier to integrate bioelectronic devices with skin-mounted patches, offering previously unheard-of functionality. In particular, sensors precisely assess the biochemical, physiological, and electrophysiological signals; actuators correctly supply the drug-loaded patch with energy; actuators then collect information about the medicine's therapeutic efficacy. This new platform for individualized therapy is made possible by the way drug-delivering patches and wearable technology work together in a full feedback loop. Because of the device's flexibility and stretchability, conformal contact with the skin needs to be protected to maximize the effectiveness of device-assisted transdermal medicine delivery. Considering the body's movements and the skin's curved morphology, the softness and The system's deformability minimize minute cracks and localized separation between both the skin and the gadget. The precise assessment of biological signals with little noise caused by motion is an additional advantage of conformally integrating a device onto the skin. This raises the wearable sensors' monitoring accuracy. physiological (like temperature, strain, and blood pressure), electrophysiology (including electroencephalograms and cardiograms), and biological signals from the skin, such as blood glucose, pH, and oxygen levels. The drug diffusion rate is controlled by a co-integrated actuator that receives information from the gathered data. A robust interface between the patch and the skin, which guarantees uniform and effective energy transfer and offers a consistent drug release profile over the whole patch region, is another way that conformal contact improves this process. Transdermal patch Additional drive skin Wearable device with signal monitoring Penetration in skin RECENT TECHNIQUES FOR TRANSDERMAL DRUG DELIVERY : Fig. 3. Various drug delivery systems Active delivery Active delivery systems react to stimulants like light, music, ultrasound, electricity, etc. Iontophoresis and electroporation are the two basic techniques used in electrically assisted delivery. Iontophoresis is carrying out a delivery of a tiny, continuous electrical current through the skin to allow charged or ionized particles to cross the natural skin barrier. The solvent's bulk flow that results from the mobile cations' favored migration Electroosmosis can transport both weakly charged and uncharged molecules. In contrast, High-voltage pulses (≥100 V) are used in iontophoresis and electroporation to make temporary skin pores. 1. Iontophoresis To enhance skin penetration and accelerate the release rate of certain drugs with low absorption/permeation profiles, iontophoresis has been demonstrated to stimulate the migration of ions across the membrane under the influence of a tiny externally applied potential difference (less than 0.5 mA/cm2). This method transports ionic or non-ionic medications in vivo by using an electrochemical potential gradient. The drug's polarity, valency, mobility, the kind of electrical cycle it delivers, and its composition all affect how well iontophoresis works. Specifically, in contrast to the majority of conventional drug delivery, the reliance on current reduces the biological characteristics that influence drug absorption through iontophoresis. To improve patient compliance, this method might also include electronic reminders for patients to adjust their dosages as needed. Electroosmosis and electron repulsion are the two kinetic mechanisms. In the former, drug molecules are subjected to an electric field, which gives them additional energy to acquire a static charge potential. As a result, they travel in a certain direction when subjected to the electric field, which permits them to pass through the epidermal barrier and enter the bloodstream and tissues. However, this method of delivering drugs necessitates extra electrode systems, power supplies, and control algorithms, which renders the devices unfit for portable development in e-skin products. Conversely, the electroosmotic mechanism entails introducing an external electric field onto the skin's surface, modifying the local distribution of electric potential, and producing electrostatic forces that drive drug molecules through the intercellular pathway and further into the skin, tissues, and bloodstream. Flexible e-skin can serve as a drug delivery medium and meet drug delivery requirements thanks to the electroosmotic process.  Fig..4. Drug release by iontophoresis 2. Sonophoresis Alternative non-invasive drug delivery techniques, such sonophoresis TDD, have been developed to lower the danger of unintentional needle injuries and the spread of infectious infections. It has been shown that the mechanical effects of sonic cavitation increase skin permeability by altering the stratum corneum's lipid structure and generating microjets and diffusion channels that physically rupture lipid bilayers. For extremely effective medication administration, sonophoresis can be coupled with other methods like dual-frequency sonophoresis or nanocarriers. However, it should be kept in mind that higher frequency can also have thermal consequences that could harm skin, such as burns, epidermal separation, and in extreme cases, necrosis of the tissue, particularly if a high thermal index is found. As a result, implementing ultrasound-based TDD requires caution. 3. Electroporation An active physical method called electroporation uses high-voltage electric pulses (between 5 and 500 V) that last for milliseconds or microseconds to transport therapeutic chemicals into cells and tissues. The drug's physicochemical characteristics and formulation variables affect the transdermal penetration efficiency caused by electroporation. Improvements in electrical properties including pulse voltage, length, and rate promote drug delivery. Delivery of biomolecules and large molecular weight hydrophilic medications is facilitated by electroporated skin. By administering high-amplitude pulses for brief periods of time, the stratum corneum's lipid bilayer structure is disrupted, leading to the formation of transient routes that facilitate drug absorption. Although electroporation presents itself as a unique medication delivery approach, it is not without its drawbacks. An electron accelerator, for example, used in drug delivery may result in local problems like bleeding, infection, and tissue cavitation. In addition, the procedure can be uncomfortable and calls for a great degree of skill and precision. Furthermore, compared to conventional drug delivery methods, the expense of electroporation equipment is rather high, which would restrict its broad use as a drug delivery strategy. 4. Photomechanical Waves The formation of transitory channels caused by photomechanical waves may have contributed to the stratum cornea's high permeability to pharmacological material. 5. Microneedle A needle is used by the novel microneedle drug delivery technology to administer medication to the circulatory system. Research is now being done on this popular transdermal medication delivery technique. Using tiny needles, the medicine is injected into the skin's outermost layer, penetrating it to the epidermal layer. By administering medicine directly to the blood capillary area, these minuscule, thin microneedles help with active absorption and pain alleviation. To date, photolithography and laser-mediated methods have been used to create microneedles. Metal or polymer microneedles can be produced via laser-mediated manufacturing processesA polymer or metal flat surface is sliced or ablated with a laser to create the three-dimensional microneedle structure. The advantage of using photolithography to precisely produce microneedles is that it may produce needles in a variety of materials and shapes. This method is most typically utilized to manufacture hydrogel, dissolving, or silicon microneedles. Based on the microneedle structure, an inverse mold is constructed using photoresist etching. There are many different kinds of prepared microneedles on the market. These include dissolving microneedles, which are composed of medication combinations that the body naturally dissolves, naturally supplied melting needles, which involve administering drugs after they have been stored in hollow needles, and drug-coated microneedles, can aid in the administration of medications coated on the needles' skin-piercing surfaces. Fig.5 - Transdermal delivery through different microneedle patches. 6. Thermal ablation By carefully heating the skin's surface, thermal ablation causes the stratum corneum to develop micropore-sized pores. If the skin is heated to hundreds of degrees for a millisecond or less, the heat is focused on the skin's surface and does not diffuse to the live tissues underneath. This keeps these tissues from being harmed or irritated. From a mechanical perspective, thermal ablation can simply mean that water in the stratum corneum is vaporized quickly, which causes volumetric expansion and ablation at the surface crater micrometer scale. Research on animals indicates that thermal ablation is a useful method for dispersing medications like human growth hormone and interferon α-2b. The skin has been heated using ohmic microheaters and radiofrequency ablation. Because thermal ablation generates tiny, localized skin injury scales, the procedure is easily tolerated. Passive delivery The term "passive delivery" describes how medications diffuse into the skin from drug reservoirs via passive diffusion or how drug reservoirs naturally biodegrade or dissolve. The effectiveness of passive distribution is influenced by the formulation's properties (hydrophobicity, charge, molecular weight, crystallinity, etc.), the quantity of active substances, and the skin's condition. For instance, anionic sodium alginate had a slower release profile when compared to cationic chitosan, which generated a considerably stronger interaction with protein agents. In vivo, hyaluronic acid (HA) is anticipated to decay far more quickly than polyesters or silk fibroin, resulting in a quicker release of the pharmaceuticals that are encapsulated. Skin factors such as skin thickness, pH, temperature, and surface bacteria can also impact the breakdown of TDDs. 1. Vesicular nanocarrier Liposomes were the first vesicular nanocarrier to be produced; They consist of a few vesicular nanocarriers' mechanisms wrapped in an aqueous core containing active ingredients. liposomes have shown inadequate transdermal penetration. Conventional phospholipid vesicles, which likewise have low skin penetration, have chemicals added to them to boost the active moiety's effectiveness at the intended location. Two more advanced vesicular carriers are niosomes, which are composed of lipid vesicles' non-ionic surfactants, and liposomes, which, in their lipophilic phase, are composed of phospholipids, while their amphiphilic nature comes from an aqueous core. Transethosomes, which are constituted by incorporating a permeation enhancer into ethosomes, and transferosomes, which consist of vesicles based on phospholipids and an edge activator. 2. Polymeric nanocarriers Drug solubility has made pharmaceutical formulation more difficult. Polymeric micelles have attracted a lot of interest as a unique way to deal with the insufficient permeability and solubility of medications via the skin. Polymeric micelles are amphiphilic, biocompatible, and biodegradable self-assembling nanocarriers composed of natural and synthetic copolymers. These nanocarriers reduce the possibility of systemic side effects, enable localized medication delivery, and encapsulate hydrophilic, lipophilic, and charged molecules. In contrast to alternative nanocarriers, they are commonly thought to possess simpler preparation and sterilizing procedures, possess a smaller size, and demonstrate superior stability across various microenvironments. 3. Nano-emulsions To address some constraints related to the topical and transdermal administration of pharmaceuticals, nano-emulsions have been developed to improve the absorption and penetration of active components while simultaneously attaining controlled release. Lipid-based colloidal oils dispersed in water are called nano- emulsions, that contain both hydrophilic and lipophilic phases and minutely distributed droplets (in the nanometer range). They provide improved solubility for both polar and non-polar molecules and are biodegradable. Since surfactants and emulsifiers are added, they have better thermodynamic and kinetic stability as well as greater lipophilic chemical bioavailability as compared to ordinary emulsions. FORMULATION AND EVALUATION ASPECTS Formulation design: Transdermal treatment systems are essentially multilaminate structures composed of the following parts: 1. Drug 2. Polymer matrix 3. Penetration enhancers 4. Adhesives 5. Backing membrane 6. Release linear. 1. Drug The necessity for regulated administration, such as a short half-life, an unpleasant effect linked to another route, or a complicated oral or IV dosing schedule, is the most crucial prerequisite for a medicine to be administered transdermally. The following categories of drug parameters can be used to identify the best candidate for transdermal drug delivery: Physicochemical characteristics 1. The molecular weight of the drug should be less than or equal to 1000 Daltons. 2. The medication needs to exhibit a preference for both hydrophilic and lipophilic phases. 3. The medication's melting point needs to be low. 4. Skin injury is prevented by using solutions in this pH range because skin varies from 4.2 to 5.6. A variety of medications may also exhibit considerable transdermal absorption at pH values where the unionized form of the pharmaceutical predominates. Biological characteristics 1. A few milligrams of the medication should be taken daily, and it should be a potent medication. 2. The medication's half-life (t2) should be brief, 3. The medication must not cause allergies or irritation 4. For drugs that break down in the gastrointestinal tract or become inactive due to the hepatic first pass effect, transdermal administration can be a helpful alternative. 2. Polymer: Modifying the composition of the polymer can adjust the release rate from TDS. A variety of membrane permeation-controlled TDS can be designed by carefully choosing the polymeric membrane. The following polymer criteria are relevant: 1) The polymer should be an inert drug carrier or chemically non-reactive 2) The polymer shouldn't break down while being stored or over time 3) A desired rate of drug dispersion must be enabled by the polymer's molecular weight, physical characteristics, and chemical functionality. 4) Both the polymer and the substance that breaks down from it should be safe. It ought to be skin-biocompatible 5) The polymer ought to be simple to work with and shape into the desired result. It ought to permit the addition of substantial amounts of active agent. 3. Penetration enhancer Enhancers boost permeability and attain higher therapeutic levels of the medication by interacting with proteins or lipids, two structural components of the stratum corneum. The improvement in skin conditions for wetting as well as trans-epidermal and trans-follicular penetration, which also promotes the absorption of oil-soluble drugs, appears to be caused by the partial leaching of the epidermal lipids by the chemical enhancers. Changing the moisture of the skin is another potential approach. 4. Adhesive layer The system has to be securely bonded to the skin's surface by the adhesive, which needs to have the right qualities to stay that way even when there is water present. Any adhesive residue that remains after the patch is removed must be removable with a water and soap wash. It is believed that adhesion is the combined result of three phenomena: 1. Peel: The ability to withstand the adhesive bond breaking; 2. Track: A polymer's capacity to stick to a substrate with minimal contact pressure and 3. Creep: Upon shearing, the adhesive bond's viscous relaxation. 5. Backing layer Drugs and permeation enhancers must be unable to pass through the backing layer. The backing membrane shields the medication reservoir from the elements., which might cause the medication to break or evaporate due to volatilization, in addition to holding the entire system together. The most often utilized supporting elements include polyester, aluminized polyethylene terephthalate, siliconized polyethylene terephthalate, and aluminum foil of metalized polyester laminated with polyethylene. 6. Release liner The peel strip prevents contamination of the finished device and stops pharmaceutical loss from moving into the adhesive layer during storage. Typical materials that are frequently utilized are foils made of polyester and other metalized laminates. EVALUATION OF TDDS: 1. The patch's width: The standard deviation and average thickness of the produced patch ensure its thickness, while the digital micrometer's mean determines the patch's breadth. Transdermal film thickness can be measured at various film sites using a screw gauge, micrometer, or microscope dial gauge. 2. Weight of uniformity Before evaluation, the patches were dried at 60 degrees Celsius for four hours. A digital balance is used to weigh each piece of the patches. Individual weights have been used to get the data for the average weight and standard deviation. 3. Folding endurance A section of a patch has been severed, and it has been folded into a similar plug multiple times till it breaks. We can determine how durable a patch is by counting how many times we can fold it from the same point before it breaks. 4. Percentage Moisture content: For a whole day, each patch is weighed separately and kept at ambient temperature in desiccators using fused calcium chloride. Following another day of patch weighting, the formula is used to determine the percentage moisture content: - 𝐼𝑛𝑖𝑡𝑖𝑎𝑙 𝑤𝑒𝑖𝑔ℎ𝑡−𝐹𝑖𝑛𝑎𝑙 𝑤𝑒𝑖𝑔ℎ𝑡 percentage moisture content= 𝐼𝑛𝑖𝑡𝑖𝑎𝑙 𝑤𝑒𝑖𝑔ℎ𝑡 5. Content uniformity test: Only ten of the patches are chosen, and the contents of each patch are predetermined. When the content of a transdermal patch falls between 75% and 125% for a single patch and between 85% and 115% for nine out of ten patches, the patch passes the content uniformity test. A second test is run with 20 patches, and if the result falls between 85% and 115%, the test is considered successful. 6. Moisture Uptake For an entire day, each patch is stored in a desiccator at room temperature. The patches were taken out and dried in desiccators with 84 percent relative humidity using a saturated potassium chloride solution till their weight became constant. after 24 hours. %Moisture uptake is calculated as: - 𝑓𝑖𝑛𝑎𝑙 𝑤𝑒𝑖𝑔ℎ𝑡−𝐼𝑛𝑖𝑡𝑖𝑎𝑙 𝑤𝑒𝑖𝑔ℎ𝑡 percentage moisture content= 𝐼𝑛𝑖𝑡𝑖𝑎𝑙 𝑤𝑒𝑖𝑔ℎ𝑡 7. Shear Adhesion test: This ascertained the adhesive polymers' cohesive strength. The stainless-steel plate is covered with an adhesive film. additionally, the amount of time needed to pull the film off the plate is measured to determine the shear adhesion strength. Its shear strength will increase with the length of time. 8. Drug content: Once the patch has been sliced, dissolve some of it in a solvent. After the solution has passed through a material for filtering, the content is determined using the proper technique, such as UV or HPLC. 9. Peel Adhesion test It takes peel adhesion to be able to take an adhesive covering off of a trial substrate. The molecular weight of the sticky polymer has an impact on it. Additionally, the test is based on the power required to remove a single coated film at a 180-degree angle from a substrate. 10. Quick stick test (peel tack test) In this test, the binding between a substrate and an adhesive at a 90-degree angle must be broken with a peel strength of 12 inches per minute. The force measured in ounces per inch width, or tack value, is given. 11. Probe Tack test: When the probe and glue come into contact, a bond is created between them. A tack is the amount of force needed to consistently remove a probe from an adhesive by pulling it at a certain distance. 12. In-vitro drug release study: This technique entails releasing the medication from the prepared patches using the paddle over-disc method (USP device (V). The patches are adhered to a glass plate with precision, weighted, and formed. The glass plate is then filled with 500 milliliters of dissolving fluid (phosphate buffer, pH 7.4). The paddle, It controls the speed up to 50 rpm. It is located 2.5 cm from the glass plate. A 5 ml sample is taken out at predetermined intervals for up to 24 hours, and it is subsequently examined using an HPLC or UV spectrophotometer. 13. In-vitro skin infusion investigation: Diffusion cells are used in this process. Take a male rat's skin; it weighs between 200 and 250 grams. The electric clipper will be used to trim the hair off the abdomen, and water will be applied to the dermal side of the skin to remove any adherent tissue and blood vessels. Before beginning an experiment, let it settle on the dissolved material for an hour, and then set it on the magnetic stirrer. The temperature is maintained at 32±0.5 degrees Celsius by the thermostatically controlled heater. The skin of the rat is placed between the diffusion cell compartment and the donor compartment, with the epidermis pointing upward. A specific volume of the sample is taken out of the receptor compartment at different times. After being removed from the filter medium, the sample is examined using an HPLC or spectrophotometer. 14. Skin-Irritation study Think about a healthy rabbit that weighs, on average, 1.2 to 1.5 kg. Next, take the hair off of the dorsal side of the rabbit. After the hair has been cut out, use rectified spirit to clean the dorsal surface before applying your formulation or skin patch. 15. Stability studies: Stability tests are conducted for six months, keeping the TDDS sample at 40± 50C and 75± 5%Rh, as per ICH guidelines. At various time intervals (e.g., 0, 30, 60, 120,  and 180), samples were taken. days), and the drug composition was looked at. In line with ICH guidelines, In the 8889 Journal of Positive School Psychology, stability tests are carried out. the TDDS sample for six months at 40± 5oC and 75± 5% Rh. Examples consist of gathered during various time periods (such as 0, 30, 60, 120, and 180 days) and their drug content is looked upon. REFERENCES :. Sun C, Bu N, Hu X. Recent trends in electronic skin for transdermal drug delivery. Intelligent Pharmacy. 2023 Aug 10.. Shingade GM. Review on: recent trend on transdermal drug delivery system. Journal of drug delivery and therapeutics. 2012 Jan 19;2(1).. Mali AD. 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